The readings listed below are the foundation of this course. Where available, journal article abstracts from
PubMed (an online database providing access to citations from biomedical literature) are included.
Readings
Adler, J. "Chemotaxis in bacteria." Science 153, 737 (1966): 708-16.
Barco, A., J. M. Alarcon, and E. R. Kandel. "Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture." Cell 108, 5 (2002): 689-703.
PubMed abstract: Restricted and regulated expression in mice of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons lowers the threshold for eliciting a persistent late phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This L-LTP has unusual properties in that its induction is not dependent on transcription. Pharmacological and two-pathway experiments suggest a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of L-LTP by a weak stimulus. Our analysis indicates that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provides insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.
Bertrand, N., D. S. Castro, and F. Guillemot. "Proneural genes and the specification of neural cell types." Nat Rev Neurosci 3, 7 (2002): 517-30.
PubMed abstract: Certain morphological, physiological and molecular characteristics are shared by all neurons. However, despite these similarities, neurons constitute the most diverse cell population of any organism. Recently, considerable attention has been focused on identifying the molecular mechanisms that underlie this cellular diversity. Parallel studies in Drosophila and vertebrates have revealed that proneural genes are key regulators of neurogenesis, coordinating the acquisition of a generic neuronal fate and of specific subtype identities that are appropriate for the location and time of neuronal generation. These studies reveal that, in spite of differences between invertebrate and vertebrate neural lineages, Drosophila and vertebrate proneural genes have remarkably similar roles.
Blair, D. F., and H. C. Berg. "Restoration of torque in defective flagellar motors." Science 242, 4886 (1988): 1678-81.
PubMed abstract: Paralyzed motors of motA and motB point and deletion mutants of Escherichia coli were repaired by synthesis of wild-type protein. As found earlier with a point mutant of motB, torque was restored in a series of equally spaced steps. The size of the steps was the same for both MotA and MotB. Motors with one torque generator spent more time spinning counterclockwise than did motors with two or more generators. In deletion mutants, stepwise decreases in torque, rare in point mutants, were common. Several cells stopped accelerating after eight steps, suggesting that the maximum complement of torque generators is eight. Each generator appears to contain both MotA and MotB.
D'Arcangelo, G., et al. "A protein related to extracellular matrix proteins deleted in the mouse mutant reeler." Nature 374, 6524 (1995): 719-23.
PubMed abstract: The autosomal recessive mouse mutation reeler leads to impaired motor coordination, tremors and ataxia. Neurons in affected mice fail to reach their correct locations in the developing brain, disrupting the organization of the cerebellar and cerebral cortices and other laminated regions. Here we use a previously characterized reeler allele (rl(tg)) to close a gene, reelin, deleted in two reeler alleles. Normal but not mutant mice express reelin in embryonic and postnatal neurons during periods of neuronal migration. The encoded protein resembles extracellular matrix proteins involved in cell adhesion. The reeler phenotype thus seems to reflect a failure of early events associated with brain lamination which are normally controlled by reelin.
Goffinet, A. M. "Developmental neurobiology. A real gene for reeler." Nature 374, 6524 (1995): 675-6.
Guthrie, S. "Axon guidance: Robos make the rules." Curr Biol 11, 8 (2001): R300-3.
PubMed abstract: A central feature of the developing nervous system is the midline region, which guides growing axons with both short- and long-range signals. New research shows that a trio of receptors, the Robos, are crucial in allowing axons to interpret these signals, ensuring correct route-finding within the emerging axon scaffold.
Hazelbauer, G. L., H. C. Berg, and P. Matsumura. "Bacterial motility and signal transduction." Cell 73, 1 (1993): 15-22.
Jarman, A. P., et al. "Atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system." Cell 73, 7 (1993): 1307-21.
PubMed abstract: In the Drosophila peripheral nervous system, proneural genes of the achaete-scute complex (ASC) are required for formation of the precursors of external sense organs but not of chordotonal organs. We report the isolation of a gene, atonal (ato), with evidence that it is a proneural gene for the formation of chordotonal organs. This gene is expressed in the proneural clusters and sense organ precursors that give rise to the embryonic and adult chordotonal, but not external sense, organs. Chordotonal organs are eliminated in embryos carrying chromosomal deficiencies that remove ato. Like the ASC products, ato protein contains a basic-helix-loop-helix region and heterodimerizes with daughterless protein to bind to E boxes. Moreover, ectopic expression of ato promotes the formation of extra sense organs. Despite similar proneural properties, we find that ectopic expression of the ASC genes promotes external sense organ formation exclusively, whereas ato promotes chordotonal organ formation preferentially. Thus, proneural genes are major determinants of neuronal identity.
Kidd, T., K. S. Bland, and C. S. Goodman. "Slit is the midline repellent for the robo receptor in Drosophila." Cell 96, 6 (1999): 785-94.
PubMed abstract: Previous studies suggested that Roundabout (Robo) is a repulsive guidance receptor on growth cones that binds to an unknown midline ligand. Here we present genetic evidence that Slit is the midline Robo ligand; a companion paper presents biochemical evidence that Slit binds Robo. Slit is a large extracellular matrix protein expressed by midline glia. In slit mutants, growth cones enter the midline but never leave it; they abnormally continue to express high levels of Robo while at the midline. slit and robo display dosage-sensitive genetic interactions, indicating that they function in the same pathway. slit is also required for migration of muscle precursors away from the midline. Slit appears to function as a short-range repellent controlling axon crossing of the midline and as a long-range chemorepellent controlling mesoderm migration away from the midline.
Konopka, R. J., and S. Benzer. "Clock mutants of Drosophila melanogaster." Proc Natl Acad Sci U S A 68, 9 (1971): 2112-6.
Macnab, R. M., and D. E. Koshland Jr. "The gradient-sensing mechanism in bacterial chemotaxis." Proc Natl Acad Sci U S A 69, 9 (1972): 2509-12.
Meister, M., G. Lowe, and H. C. Berg. "The proton flux through the bacterial flagellar motor." Cell 49, 5 (1987): 643-50.
PubMed abstract: Bacterial flagella are driven by a rotary motor that utilizes the free energy stored in the electrochemical proton gradient across the cytoplasmic membrane to do mechanical work. The flux of protons coupled to motor rotation was measured in Streptococcus and found to be directly proportional to motor speed. This supports the hypothesis that the movement of protons through the motor is tightly coupled to the rotation of its flagellar filament. Under this assumption the efficiency of energy conversion is close to unity at the low speeds encountered in tethered cells but only a few percent at the high speeds encountered in swimming cells. This difference appears to be due to dissipation by processes internal to the motor. The efficiency at high speeds exhibits a steep temperature dependence and a sizable deuterium solvent isotope effect.
Nakazawa, K., et al. "Requirement for hippocampal CA3 NMDA receptors in associative memory recall." Science 297, 5579 (2002): 211-8.
PubMed abstract: Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.
Nitabach, M. N., J. Blau, and T. C. Holmes. "Electrical silencing of Drosophila pacemaker neurons stops the free- running circadian clock." Cell 109, 4 (2002): 485-95.
PubMed abstract: Electrical silencing of Drosophila circadian pacemaker neurons through targeted expression of K+ channels causes severe deficits in free-running circadian locomotor rhythmicity in complete darkness. Pacemaker electrical silencing also stops the free-running oscillation of PERIOD (PER) and TIMELESS (TIM) proteins that constitutes the core of the cell-autonomous molecular clock. In contrast, electrical silencing fails to abolish PER and TIM oscillation in light-dark cycles, although it does impair rhythmic behavior. On the basis of these findings, we propose that electrical activity is an essential element of the free-running molecular clock of pacemaker neurons along with the transcription factors and regulatory enzymes that have been previously identified as required for clock function.
Oosawa, K., J. F. Hess, and M. I. Simon. "Mutants defective in bacterial chemotaxis show modified protein phosphorylation." Cell 53, 1 (1988): 89-96.
PubMed abstract: To examine the correlation between CheA phosphorylation and bacterial chemotaxis, cheA mutations leading to defects in chemotaxis were mapped and characterized. Mutant CheA proteins were tested in vitro for phosphorylation and were grouped into four classes: nonphosphorylated, partially phosphorylated, phosphorylated but not dephosphorylated by CheB and CheY, and phosphorylated and dephosphorylated. Nearly all the mutants were found to be defective in an aspect of phosphorylation. Furthermore, the mutant phenotypes were found to cluster in different regions of the cheA gene. We suggest that the CheA protein has three functional domains: one for interaction with CheB and CheY, a second for regulating phosphorylation and controlling the stability of the protein, and a third for receiving input signals regulating CheA activity.
Panda, S., J. B. Hogenesch, and S. A. Kay. "Circadian rhythms from flies to human." Nature 417, 6886 (2002): 329-35.
PubMed abstract: In this era of jet travel, our body 'remembers' the previous time zone, such that when we travel, our sleep wake pattern, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of time displacement until we adjust to the new time zone. Although the existence of a circadian clock in humans had been postulated for decades, an understanding of the molecular mechanisms has required the full complement of research tools. To gain the initial insights into circadian mechanisms, researchers turned to genetically tractable model organisms such as Drosophila.
Salzberg, A., et al. "Mutations affecting the pattern of the PNS in Drosophila reveal novel aspects of neuronal development." Neuron 13, 2 (1994): 269-87.
PubMed abstract: Through a systematic genetic screen, we have identified 55 mutations that affect the development of the PNS of Drosophila embryos. These mutations specify 13 novel and 5 previously characterized genes and define new phenotypes for 2 other known genes. Five classes of mutant phenotypes were identified in the screen: gain of neurons, loss of neurons, abnormal position of chordotonal neurons, aberrant neuronal trajectories, and abnormal morphology of neurons. Phenotypic analyses of mutations identified in this study revealed three novel aspects of PNS development. First, we have identified a novel gene that may be required to define glial versus neuronal cell identity. Second, our data indicate that neuronal migration plays an important role in pattern formation in the embryonic PNS. Third, we have identified mutations that cause a lack of sensory organs, but unlike mutations in proneural genes, do not affect the formation of sensory organ precursors. These genes may be required for key aspects of neuronal differentiation. Our studies suggest that approximately 70 essential genes are required for proper PNS development in Drosophila embryos.
Simpson, J. H., et al. "Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position." Cell 103, 7 (2000): 1019-32.
PubMed abstract: Slit is secreted by midline glia in Drosophila and functions as a short-range repellent to control midline crossing. Although most Slit stays near the midline, some diffuses laterally, functioning as a long-range chemorepellent. Here we show that a combinatorial code of Robo receptors controls lateral position in the CNS by responding to this presumptive Slit gradient. Medial axons express only Robo, intermediate axons express Robo3 and Robo, while lateral axons express Robo2, Robo3, and Robo. Removal of robo2 or robo3 causes lateral axons to extend medially; ectopic expression of Robo2 or Robo3 on medial axons drives them laterally. Precise topography of longitudinal pathways appears to be controlled by a combination of long-range guidance (the Robo code determining region) and short-range guidance (discrete local cues determining specific location within a region).
Stefansson, H., et al. "Neuregulin 1 and susceptibility to schizophrenia." Am J Hum Genet 71, 4 (2002): 877-92.
PubMed abstract: The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.
Tessier-Lavigne, M., and C. S. Goodman. "The molecular biology of axon guidance." Science 274, 5290 (1996): 1123-33.
PubMed abstract: Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
Tobin, A. J., and E. R. Signer. "Huntington's disease: the challenge for cell biologists." Trends Cell Biol 10, 12 (2000): 531-6.
PubMed abstract: Huntington's disease (HD) is one of eight inherited neurodegenerative diseases caused by expansions of (CAG)(n) tracts that encode polyglutamine segments in expressed proteins. Studies of pathogenic mechanisms for all these late-onset diseases suffer from a common drawback: experimental studies require massive acceleration of a process that, in affected humans, usually takes decades. But is the rapid-onset disease of transgenic mouse models and in cells the same as the slow-onset disease in humans? We review recent work on HD, noting several issues whose significance is likely to be crucial - but which are as yet unresolved. We discuss these in light of the distinction between disease-specific pathogenic mechanisms and artifacts of polyglutamine overexpression. We suggest that the initial stages of HD result from dysfunction rather than death, and we consider the potential discovery of compounds that might interfere with early pathogenic events.
Yamamoto, A., J. J. Lucas, and R. Hen. "Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease." Cell 101, 1 (2000): 57-66.
PubMed abstract: Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible.